Stuart A. Montgomery

Treatment resistant depression: methodological overview and operational criteria

A wide variety of definitions are used for Treatment Resistant Depression (TRD), considering various criteria and different concepts. Some of the key issues are: the diagnosis, the treatment adequacy in terms of dose and duration, the treatment response assessment and the number of failed therapeutic trials required. Systematic research has been characterizing the concept and criteria to define the different variables involved. Lack of consensus on these issues limits comparison across clinical trials and interpretation of treatment efficacy in the management of treatment resistant patients. Through reanalyzes of available data, we point out the limits of TRD definitions and propose conceptual and operational criteria for a collaborative research project on TRD. It appears that a number of variables commonly associated to treatment resistance are independent of patients characteristics and mainly refer to misdiagnosis and inadequate treatment. The proposed criteria are intended for therapeutic trials in TRD, combining the evaluation of treatment efficiency and the validation of the concept of TRD itself. Major depression with poor response to two adequate trials of different classes of antidepressants is proposed for an operational definition of TRD. Rationale for this definition is discussed in contrast to alternative definitions.

Lack of Efficacy of the Substance P (Neurokinin1 Receptor) Antagonist Aprepitant in the Treatment of Major Depressive Disorder

BACKGROUND An early clinical trial suggested that the substance P (neurokinin(1) receptor) antagonist, aprepitant, might provide a unique mechanism of antidepressant activity. Phase III trials were conducted to confirm these findings. METHODS Five 8-week, randomized, double-blind, parallel-groups, placebo-controlled, multicenter trials in outpatients with Major Depressive Disorder were performed. Aprepitant 160 mg and placebo were included in all trials. Aprepitant 80 mg and paroxetine 20 mg (active comparator) were included in three trials. Approximately 150 patients were enrolled per treatment group in each trial. The primary end point was the mean change-from-baseline of the first 17 items of the Hamilton Rating Scale for Depression (HAM-D(17)) score at 8 weeks. A positron emission tomography (PET) study was also performed in normal subjects to determine the relationship between neurokinin(1) receptor occupancy and aprepitant plasma concentrations in dosing regimens relevant to the trials. RESULTS No statistically significant differences from placebo on the HAM-D(17) were observed at week 8 for either dose of aprepitant in any of the trials, whereas paroxetine 20 mg was significantly (p <or= .05) more effective than placebo at week 8 in each of the three trials in which it was included. Results from the PET study indicated that the aprepitant dosing regimens provided continuously high levels of neurokinin(1) receptor blockade over 8 weeks. CONCLUSIONS Because the methodology employed confirmed the antidepressant efficacy of paroxetine, the absence of an effect for aprepitant indicates that it was not an effective treatment for depression. The concept of neurokinin(1) receptor antagonism as an antidepressant mechanism was not supported.

Prevalence of anxiety disorders comorbidity in bipolar depression, unipolar depression and dysthymia

Eighty-seven patients with current episode of depression were assessed by the SCID-P and subdivided in bipolar depressives (N = 24), unipolar depressives (n = 38) and dysthymics (n = 25). Anxiety disorders comorbidity in these three groups was investigated by means of the SCID-P. Panic disorder comorbidity was found in 36.8% of bipolar depressives, 31.4% of unipolar depressives and 13% of dysthymics. Prevalence of obsessive-compulsive disorder was 21.1% in bipolars, 14.3% in unipolars and 8.7% in dysthymics. Generalized anxiety disorder resulted in being much more associated with dysthymia (65.2%) than with bipolar (31.6%) or unipolar depression (37.1%). Social phobia comorbidity was exhibited mainly by unipolars (11.4%), while no cases were detected in the bipolar group. Odds ratios revealed that generalized anxiety disorder is significantly more likely to co-occur with dysthymia. Panic disorder showed a higher trend to be associated with bipolar and unipolar depression. Social phobia was more frequent among unipolar depression.

Pharmacological prevention of suicidal behaviour

The number of hospital admissions following an episode of deliberate self harm has been increasing steadily over the past two decades and hospitals in England and Wales now provide care for some 100,000 cases of deliberate non-fatal self-poisoning per year. Indeed in younger women self-poisoning is the commonest cause of emergency admission to a medical ward. The rate of actual suicide has not changed very much although the unreliable nature of suicide statistics and reporting bias make it difficult to make categorical statements. Those with a history of suicidal behaviour contribute substantially to the suicide rates. In this group subsequent suicidal behaviour is reported in 20% within one year (Kreitman 1977). Estimates of the subsequent suicide rate in this group range from 1 to 2% per annum which is between a hundred and two hundred times the expected rate for the general population. Whether they die or not these patients with suicidal behaviour are an at risk group associated with considerable suffering both for themselves and their friends and family. A strong association between suicide and depression has been assumed largely on the basis of retrospective analysis, which is subject to the bias inherent in even the most carefully conducted investigations. Prospective surveys of the prevalence of psychiatric illness in patients admitted to hospital following an episode of deliberate self harm vary but there is agreement that it appears to account for no more than around 40% of such admissions. In the Edinburgh survey depressive illness was a common diagnosis but accounted for only 28% of the men and 40% of the women. By far the largest category were patients with personality disorders. It is likely that any investigation of suicidal behaviour will need to look at the phenomenon in personality disorders separately from depressed patients.

Antidepressant medications: a review of the evidence for drug-induced sexual dysfunction

BACKGROUND Sexual dysfunction is recognised as a potential side effect of antidepressant therapy. However, there is little detailed information on the prevalence of drug-induced sexual dysfunction or the differences, if any, between available drugs. This article is a critical review of the literature in the area. METHODS English-language studies on sexual dysfunction and depression or antidepressant treatments were identified by searching Medline and supplemented by manual review of their reference lists and recent journal issues available in a library. Trials of antidepressant use in anxiety disorders were identified from a Medline search and their adverse events tables scanned for data on sexual dysfunction. All trials were assessed according to predefined criteria. RESULTS Sexual dysfunction is widespread in the healthy non-depressed population and is a recognised symptom of depression and/or anxiety disorders. Sexual dysfunction has been reported with all classes of antidepressants (MAOIs, TCAs, SSRIs, SNRIs and newer antidepressants) in patients with depression and various anxiety disorders. Numerous studies have been published, but only one used a validated sexual function rating scale and most lacked either a baseline or a placebo control or both. None met all of the pre-defined assessment criteria. LIMITATIONS The search techniques may have missed some studies and publication bias cannot be ruled out. CONCLUSIONS The existing literature confirms sexual dysfunction as a possible adverse event of all antidepressants, but it is not sufficiently robust to support claims for differences in the incidence of drug-induced sexual dysfunctions between existing antidepressant therapies. Prescribing decisions should be based on a careful assessment of the benefits and risks of therapy in the individual patient.

A double-blind, placebo-controlled study of fluoxetine in patients with DSM-III-R obsessive-compulsive disorder

We have studied the effect of three fixed daily doses of fluoxetine in patients with obsessive-compulsive disorder (OCD) diagnosed according to DSM-III-R. Two hundred and fourteen patients were evaluated in an 8-week double blind, placebo-controlled study. A statistically significantly greater number of fluoxetine-treated patients achieved the prospectively defined criteria for clinical response when compared to placebo treatment. There was a statistically significant overall difference in the PGI rating of symptom change (P = 0.045) and a marginally significant difference (P = 0.089) in the CGI severity rating between groups. Pairwise comparison against placebo showed a marginally statistically significantly greater improvement (P = 0.059) in Y-BOCS-Total score for patients receiving fluoxetine 60 mg daily, and a significantly higher response rate in patients receiving fluoxetine 40 mg or 60 mg daily (P<0.05). One hundred and sixty one patients continued to a 16-week extension evaluation. There was no significant difference in the rate of reporting of any individual adverse event between placebo and fluoxetine, and the rate of discontinuation due to adverse events was low (< 6% in each study phase). This study supports the growing evidence for the safety and efficacy of fluoxetine in the treatment of OCD.

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders, Part III: Maintenance Treatment

Summary As with the two preceding guidelines of this series, these practice guidelines for the pharmacological maintenance treatment of bipolar disorder were developed by an international task force of the World Federation of Societies of Biological Psychiatry (WFSBP). Their purpose is to supply a systematic overview of all scientific evidence relating to maintenance treatment. The data used for these guidelines were extracted from a MEDLINE and EMBASE search, from recent proceedings from key conferences and various national and international treatment guidelines. The scientific justification of support for particular treatments was categorised into four levels of evidence (A-D). As these guidelines are intended for clinical use, the scientific evidence was not only graded, but also reviewed by the experts of the task force to ensure practicality.

A 24-week study of 20 mg citalopram, 40 mg citalopram, and placebo in the prevention of relapse of major depression.

A total of 147 patients who had responded in a placebo-controlled study to 6 weeks treatment of an episode of DSM-III-R major depression with either 20 mg or 40 mg citalopram were randomized double-blind to continue on the same dose of citalopram or to receive placebo during a 24-week study of the efficacy of citalopram in the prevention of relapse. The citalopram 20 and 40 mg groups showed a significant advantage compared with placebo both in relapses (p < 0.05) and in the survival analysis of time to relapse (p = 0.01 and p = 0.02, respectively). Both 20 and 40 mg citalopram appeared similarly safe and well tolerated with little difference in side effects from placebo. The results demonstrate that citalopram, at a dose of both 20 and 40 mg is effective and well tolerated in continuation treatment to consolidate response. The relapse rate in patients who had responded to placebo during the 6-week acute treatment study, who were continued double-blind with placebo but not included in the efficacy analysis, was similar to the rate in the formal placebo control group, suggesting that patients who respond to placebo in a short treatment course may nonetheless require long-term active treatment to prevent relapse.

A Randomised Study Comparing Escitalopram with Venlafaxine XR in Primary Care Patients with Major Depressive Disorder

This 8-week, randomised, double-blind study compared the efficacy and tolerability of escitalopram to that of venlafaxine XR in primary care patients with major depressive disorder. The efficacy of escitalopram (10– 20 mg; n = 148) was similar to venlafaxine XR (75– 150 mg; n = 145), based on mean change from baseline to week 8 in Montgomery and Åsberg Depression Rating Scale total score. In ad hoc analyses, escitalopram-treated patients achieved sustained remission significantly faster than did venlafaxine-treated patients. More venlafaxine-treated patients had nausea, constipation, and increased sweating (p < 0.05). When treatment was completed after 8 weeks, significantly more venlafaxine-treated patients had discontinuation symptoms (p < 0.01). Thus escitalopram treatment was similar to venlafaxine treatment with respect to efficacy and was better tolerated by patients in primary care.

The role of noradrenaline and selective noradrenaline reuptake inhibition in depression.

Depression is a common disorder that impacts on all aspects of a persons life. For the past 10 years, clinicians have focused on serotonin in their treatment of depression. This is largely due to the growing acceptance of the efficacy and safety of the selective serotonin reuptake inhibitors (SSRIs) in comparison with older tricyclic antidepressants (TCAs). However, evidence for a role of noradrenaline in depression has been accumulating for some time, beginning with the discovery that drugs which either caused or alleviated depression acted to alter noradrenaline metabolism. Until recently, the role of noradrenaline in depression was predicted from clinical experience with noradrenergic TCAs (desipramine, nortriptyline and protriptyline) and selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, milnacipran). The licensing of reboxetine, a selective noradrenaline reuptake inhibitor now allows the role of noradrenaline in depression to be investigated directly. This review presents key data from the literature that support a role for noradrenaline in depression taking into account neurophysiology, psychopharmacology and clinical trial data.